Dopamine (DA) is a neurotransmitter that plays an essential role in normal brain functions. As a chemical messenger, dopamine is similar to adrenaline. In the brain, dopamine is synthesized in the pre-synaptic neurons and released into the space between the pre-synaptic and post-synaptic neurons.
Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Therefore, the regulation of dopamine plays an important role in mental and physical health. Neurons containing dopamine are clustered in the midbrain area called the substantia nigra. Abnormal dopamine signaling in the brain has been implicated in a substantial number of pathological conditions, including drug (e.g., cocaine) abuse, depression, anxiety, schizophrenia, Tourette's syndrome, eating disorders, alcoholism, chronic pain, obsessive compulsive disorders, restless leg syndrome, Parkinson's Disease, and the like.
Dopamine molecules bind to and activate dopamine receptors on the post-synaptic neurons. Dopamine molecules then are transported through the dopamine transporter protein (DAT) back into the pre-synaptic neurons, where they are metabolized by monoamine oxidase (MAO). In conditions such as cocaine abuse, cocaine binds to the dopamine transporter and blocks the normal flow of dopamine molecules. Excess concentrations of dopamine cause over-activation of dopamine receptors. In other conditions, such as Parkinson's Disease, lack of sufficient dopamine receptors in the brain causes insufficient activation of dopamine receptors.
Dopaminergic neurotransmission is mediated by five dopamine receptors (D1-D5), which can be grouped into the D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptor subtypes. The dopamine 3 (D3) subtype receptor has been implicated as an important target for agents currently used clinically for the treatment of schizophrenia, Parkinson's disease, depression, and other neurological diseases.(1)-(4) Studies have also provided strong evidence that potent and selective D3 ligands may have a therapeutic potential as pharmacotherapies for the treatment of drug abuse.(5)-(8) Therefore, considerable effort has been devoted to the discovery and development of potent and selective D3 ligands.(7)-(33) 
A number of representative potent and selective D3 ligands (antagonists, partial agonists and full agonists) are shown in FIG. 1. These D3 ligands bind to the D3 receptor with a very high affinity (Ki values of ≦1.0 nM) and display a selectivity of 100-500 times over the D2 receptor and greater than 1,000 over the D1-like receptors when evaluated in in vitro binding assays either using cloned human dopamine receptors or rat brain.(7),(8) 
SB-277011A (1) is a potent and selective D3 antagonist(9) and has been used extensively in animals to investigate the role of the D3 receptor in drug abuse.(8) One disadvantage of SB-277011A is that relatively high doses are needed to produce an in vivo effect, suggesting a moderate central nervous system (CNS) penetration. SB-414796 (2) is a potent and selective D3 antagonist and has an excellent bioavailability in the rat and a good CNS penetration.(16) However, compound 2 did not advance into clinical development because of its inhibition of p450 and its potential cardiotoxicity due to a strong binding to hERG potassium channel.(8),(32) Very recently, compound 3 was designed as a highly potent and selective D3 antagonist.(32) Compound 3 has an excellent oral bioavailability and good CNS penetration. Importantly, compound 3 only shows weak inhibition on all the P450 isoforms and a large selectivity window with respect to their affinity at the hERG channel, overcoming the major issues associated with compound 2. BP 897 (4) initially was described as a potent D3 partial agonist with a modest selectivity of less than 100-times over D2,(6) but subsequent studies have shown that compound 4 may behave as an D3 antagonist.(34),(35) NGB 2904 (5) is a potent and selective D3 antagonist(10) and has been extensively used in vivo evaluations, despite its poor aqueous solubility.(8) In order to improve D3 selectivity and water solubility, a large number of new analogues have been designed and synthesized, including compounds 6,(18), 7(30) and 8(30). Compound 8 is a potent D3 antagonist and displays a selectivity of greater than 400-fold over D2 in in vitro binding assays.(30) Compound 8 has a much improved solubility compared to compound 5.(30) 
One challenge in the design and development of D3 ligands has been a lack of the correlation between the intrinsic in vitro activity and in vivo activity for many reported D3 ligands. This was due in part to a lack of well validated in vivo functional assays for the D3 and D2 receptors. To this end, yawning and hypothermia functional assays for the D3 and D2 receptors in the rat have been validated.(36),(37) Data clearly show that while D3 agonist activity induces yawning in the rat, D2 agonist activity inhibits yawning induced by the D3 agonist activity.(36),(37) Furthermore, while D2 agonist activity decreases the body core temperature in the rat, D3 agonist activity has no effect on the body core temperature.(36),(37) 
A number of known D3 ligands were evaluated in the yawning and hypothermia assays. It was found that many of the potent and selective D3 ligands based upon in vitro data, such as compounds 1, 4, 5 and 9, have a narrow range of selectivity in vivo at the D3 receptor over the D2 receptor, typically less than 10-fold.(36),(37) This narrow range of in vivo selectivity for the D3 receptor over the D2 receptor makes the interpretation of in vivo behavioral data for many known D3 ligands complicated and highlights the need for highly potent D3 ligands with a large in vivo selectivity for D3 over D2.
Many reported potent and selective D3 ligands based upon their in vitro data have very poor aqueous solubility, which contributes to their low in vivo activity and selectivity.(7),(8) To address the solubility issue, a series of new compounds based upon the core structure of pramipexole (compound 9), a highly potent D3 full agonist with excellent aqueous solubility but a modest selectivity for the D3 receptor over the D2 receptor, were designed and synthesized.(25) Another consideration for using pramipexole as the basic core structure is that pramipexole is an FDA approved drug for the treatment of Parkinson's disease and restless leg syndrome, and has an excellent safety and pharmacological properties in the human.
Accordingly, a need still exists in the art for potent and selective D3 ligands having physical and pharmacological properties that permit use of the ligands in therapeutic applications. The present invention provides ligands designed not only to selectively bind to the D3 receptor subtype in in vitro binding assays, but also modulate (e.g., agonism and/or antagonism) the D3 receptor with high selectivity in vivo functional assays in the rat.